Type-2 diabetes (“T2D”) is one of the most common chronic diseases afflicting humans. The hallmark of T2D is abnormally elevated blood glucose levels. Further, dyslipidemia is encountered in many T2D patients. Dyslipidemia typically manifests itself as elevated Low Density Lipoprotein (LDL), depressed High Density Lipoprotein HDL levels and elevated triglyceride levels. About 79 million Americans ages had prediabetes, a predisposition to develop diabetes, about 1.9 million cases of Americans ages were newly diagnosed with T2D adding to the 25.6 million, or 11.3 percent, of Americans with T2D in the United States according to the U.S. Department of Health and Human Services' estimates. As T2D progresses the regulation of blood glucose levels falters to the point of requiring supplemental insulin. Sedentary lifestyles are believed to be responsible for the increase in T2D, but, on the other hand, the conventional wisdom holds that making lifestyle changes is impractical. Thus, T2D is one of the more pressing health problems treated imperfectly by medications.
As to consequences of T2D, PostPrandial HyperGlycemia (PPHG), but not Fasting HyperGlycemia (FHG), appears to independently predict the occurrence of cardiovascular disease (CVD) events. In addition sustained abnormally high glucose levels (Hyperglycemia) are associated with the long term increase in the risk of strokes, blindness, thickening of the skin, dry skin, infections, and the like. Thus, T2D negatively impacts both mortality and quality of life.
Considerable effort has been expended in developing better medications. Most T2D patients are treated with a combination of medications with most combinations exhibiting risk of hypoglycemia. The least risk of hypoglycemia is with excretagogues and carbohydrate digestion/absorption inhibitors—provided they are not combined with other medications. The medications fall in many classes such as (i) secretagogues (e.g., Sulfonylureas and Meglitinide), (ii) insulin sensitizers (also known as Thiazolidinediones), (iii) gluconeogenesis inhibitors (Biguanides and Dipetidyl peptidase-4 inhibitors), (iv) excretagogues (SGLT2 inhibitors), and (v) carbohydrate digestion/absorption inhibitors (alpha glucosidase inhibitors). There are in development medications/devices to control appetite by manipulating satiety etc. and surgical weight loss procedures—that cure T2D in about half of the patients.
For drugs approved for treating T2D, the Food and Drug Administration (“FDA”) requires that their labels include language stating that the medication “is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus”. How this is to be implemented in practice is still an unsolved problem.
Most medication for treating T2D increase the risk of hypoglycemia. For instance, extra exercise, a smaller or missed meal, or an infection can reduce blood glucose levels dangerously when diabetes is controlled primarily with medications. T2D patients may end up in the Emergency Room due to a minor infection—fighting which suddenly may have consumed plasma glucose with replenishment inhibited by their medications resulting in hypoglycemia and a visit to the Emergency Room. Although exercise is recommended, it is not advisable without close supervision in T2D patients due to the risk of hypoglycemia. Effectively exercise is contraindicated for T2D patients being treated with conventional medications—other than the new class of SGLT2 inhibitors. The latter carry the increased risk of urinary infections and possible elevation of creatinine levels. Thus, for most medication combinations levels physicians choose some hyperglycemia to guard against hypoglycemia.
With the possible exception of the glucagon-like peptide 1 analogs and the thiazolidinediones, which lose their effectiveness eventually as well, other antidiabetic medications lose their effectiveness to control hyperglycemia over time. Therefore, in view of the difficulty in achieving optimal glycemic control for T2D patients using current therapies, there is an unmet medical need for new antidiabetic treatments, particularly those that can reverse the irresistible disease progression.
The HbA1c test provides an indication of the average blood glucose levels over about three months to help evaluate the efficacy of a blood glucose control regime. It has become the de facto standard for diagnosis and evaluation of T2D treatments, but this has reduced the utility for T2D patients of sophisticated home glucose measuring instruments other than for confirming the infrequent hypoglycemia events. Naturally, attempts at developing a commercially successful and medically useful non-invasive blood glucose meter, i.e., requiring no skin punctures, have mostly failed because of their difficulty in reliably detecting hypoglycemia. Bodily fluids (such as saliva, sweat, urine, tears) have glucose at about one fiftieth or even less of that in blood/plasma. Thus, for non-invasive glucose meters the unmet challenge has been to accurately and reliably distinguish between about 70 mg/dL, which is the low end of the ‘normal’ blood glucose levels and about 60 mg/dL, when hypoglycemia sets in and flag 50 mg/dL levels as dangerous due to impairment of cognitive abilities.
U.S. Pat. No. 6,102,872 by Doneen et al. discloses a saliva based glucose measuring instrument. The '872 patent discloses detection of glucose levels in saliva when blood glucose levels were at about 100 mg/dL. U.S. Pat. No. 8,898,069 by Hood et al. discloses additional salivary glucose detection embodiments using a device enclosed in the oral cavity. US Published Patent Application No. US 2014/0197042 A1 by Zhang et al. discloses measurement of salivary glucose with a resolution of about 0.5 mg/dL with a lower limit of detection at about 1.5 mg/dL corresponding to blood/plasma levels of about 100 mg/dL. Saliva based glucose detection is being developed and tested by QUICK LLC. Some noninvasive meters also use combination of spectroscopic techniques, such as the GlucoTrack meter. These, naturally are very expensive compared to the practice of almost giving away meters that use strips—with the revenue from sales of strips providing the required return but need less consumables. With periodic HbA1c measurements dramatically reducing the utility of regular glucose monitoring in T2D patients, in effect, glucose meters are primarily sustained by their use by diabetics, who do need insulin to control their glucose levels.
Unmet remains the medical need for new and, more importantly, effective antidiabetic treatments for T2D to reverse its irresistible progression under the current treatment strategies.